Structural Basis of Broad HIV Neutralization by a Vaccine-Induced Cow Antibody

Summary

Potent broadly neutralizing antibodies (bnAbs) to HIV have been very challenging to elicit by vaccination in wild-type animals. Here, by x-ray crystallography, cryo–electron microscopy, and site-directed mutagenesis, we structurally and functionally elucidate the mode of binding of a potent bnAb (NC-Cow1) elicited in cows by immunization with the HIV envelope (Env) trimer BG505 SOSIP.664.

The exceptionally long (60 residues) third complementarity-determining region of the heavy chain (CDR H3) of NC-Cow1 forms a mini domain (knob) on an extended stalk that navigates through the dense glycan shield on Env to target a small footprint on the gp120 CD4 receptor binding site with no contact of the other CDRs to the rest of the Env trimer.

These findings illustrate, in molecular detail, how an unusual vaccine-induced cow bnAb to HIV Env can neutralize with high potency and breadth.

Highlights

• Cows may be particularly useful for vaccine testing and optimization.
• Engineered vaccines could be rapidly tested for efficacy in cows to validate epitope presentation and construct integrity.
• The isolated cow knob domains might also be engineered as small protein inhibitors of antigens of interest.
• In emerging virus outbreak, rapid generation of bovine sera may help in patient treatment.
• A better understanding of the bovine immune system may also aid in design of vaccines or treatments for cows themselves.
• Bovine species live alongside humans throughout the world and, unlike other model species, should be readily available for immunization trials at or near locations of a viral outbreak.